Use of molecular biomarkers to quantify the spatial distribution of effects of anticancer drugs in solid tumors
Menée à l'aide de xénogreffes, d'anticorps monoclonaux et de techniques d'immunohistochimie, cette étude met en évidence la distribution des agents anticancéreux à l'intérieur des tumeurs solides peu après leur injection dans la circulation sanguine
Poor distribution of anticancer drugs within solid tumors may limit their effectiveness. Here we characterize the distribution within solid tumors of biomarkers of drug effect. γH2aX, cleaved-caspase -3 or -6 and Ki-67 were quantified in tumor sections in relation to blood vessels (recognized by CD31) using monoclonal antibodies and immunohistochemistry. To validate their use we compared their time-dependent distribution with that of (i) fluorescent doxorubicin and (ii) a monoclonal antibody that detects melphalan-induced DNA adducts. The biomarkers were then used to quantify the distribution of docetaxel in relation to tumor blood vessels. Activation of γH2aX was evaluated following in vitro exposure of tumor cells to multiple drugs. Distributions of doxorubicin in MDA-MB-231 and MCF-7 xenografts and of melphalan-induced DNA adducts in MCF-7 & EMT-6 tumors decreased with distance from blood vessels, similar to the distributions of (i) γH2aX at 10 minutes, (ii) cleaved caspase-3 or -6 and (iii) change in Ki-67 at 24 hours following treatment. The distribution of these biomarkers following treatment with docetaxel also decreased with increasing distance from tumor blood vessels. Activation of γH2aX occurred within 1 hour after exposure to several drugs in culture. Multiple anticancer drugs show a decrease in activity with increasing distance from tumor blood vessels; poor drug distribution is an important cause of drug resistance. The above biomarkers may be employed in designing strategies to overcome therapeutic resistance by modifying or complementing the limited spatial distribution of drug activity in solid tumors.
http://mct.aacrjournals.org/content/early/2013/01/24/1535-7163.MCT-12-0967.abstract